(a) Field of the Invention
This invention in its broadest aspect relates to inhibitors of metabolic pathways. In particular, the invention relates to novel compounds of Formula I, which are inhibitors of leukotriene D.sub.4 (LTD.sub.4) and which therefore are useful to prevent or allleviate the symptoms associated with LTD.sub.4, such as allergic reactions, particularly asthma, see M. Griffin et al., N. Engl. J. Med., 308, 436 (1983); inflammatory conditions; and coronary vasoconstriction.
LTD.sub.4 is a product of the 5-lipoxygenase pathway and is the major active constituent of slow reacting substance of anaphylaxis (SRS-A), a potent bronchoconstrictor that is released during allergic reactions. See R. A. Lewis and K. F. Austen, Nature, 293, 103-108 (1981). When administered to humans and guinea pigs, LTD.sub.4 causes bronchoconstriction by two mechanisms: (1) directly by stimulating smooth muscle; and (2) indirectly through release of thromboxin A.sub.2, which causes contraction of respiratory smooth muscle. Because antihistamines are ineffective in the management of asthma, SRS-A is believed to be a mediator of the bronchoconstriction occurring during an allergic attack. LTD.sub.4 may also be involved in other inflammatory conditions such as rheumatoid arthritis. Furthermore, LTD.sub.4 is a potent coronary vasoconstrictor and influences contractile force in the myocardium and coronary flow rate of the isolated heart. See F. Michelassi et al., Science, 217, 841 (1982); J. A. Burke et al., J. Pharmacol. and Exp. Therap., 221, 235 (982).
(b) Prior Art
A number of aryloxyalkoxy benzopyrans and benzopyranones have been disclosed as useful leukotriene inhibitors. See, e.g., U.S. Pat. Nos. 4,238,495, 4,213,903, 4,006,245, and 3,953,604; British Pat. No. 1,291,864; and R. A. Appleton et al., J. Med. Chem., 20, 371-379 (1977). The compounds of this invention represent the first class of LTD.sub.4 inhibitors in which a pyranone moiety is not ring-fused to a benzene ring and is instead attached directly to an aryloxyalkoxy or aralkoxy substituent.